Aerobic Exercise Activates Fibroblast Growth Factor 21 and Alleviates Cardiac Ischemia/Reperfusion-induced Neuronal Oxidative Stress and Ferroptosis in Paraventricular Nucleus

Cardiac ischemia/reperfusion (I/R) induces systemic oxidative stress, which in turn gives rise to the development of multiple organ abnormalities, including brain injury. The paraventricular nucleus (PVN) of the hypothalamus is a cardiovascular regulatory center. Aerobic exercise is an effective intervention to protect the heart against I/R injury. However, the effect of aerobic exercise on cardiac I/R-induced neuronal injury in the PVN has not been fully elucidated. The aim of this study is to investigate whether aerobic exercise can up-regulate Fibroblast Growth Factor 21 (FGF21) and alleviate neuronal oxidative stress and Ferroptosis in the PVN caused by cardiac I/R. In vivo, after six weeks of aerobic exercise, the cardiac I/R model was established by ligating the left anterior descending (LAD) coronary artery for 30 min, followed by 2 h of reperfusion. Cardiac function and heart rate variability (HRV) were measured. Morphological changes, oxidative stress, expression of FGF21 and its downstream signaling molecules, as well as ferroptosis-related indicators in the PVN, were evaluated. In vitro, HT22 cells were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) and treated with recombinant human FGF21 (rhFGF21) and compound C to elucidate the potential mechanism. Cardiac I/R induced iron deposition, elevated expression of lipid peroxidation drivers, and impaired antioxidant capacity in the PVN, which collectively contributed to neuronal Ferroptosis. Aerobic exercise up-regulated the expression of FGF21, FGFR1, and PGC-1α, maintained the phosphorylation of AMPKα, enhanced antioxidant capacity, reduced ROS and lipid peroxidation, regulated iron homeostasis, and effectively attenuated neuronal Ferroptosis induced by cardiac I/R. In addition, rhFGF21 protected HT22 cells against OGD/R-induced oxidative stress and Ferroptosis, which was blocked by AMPK inhibition. FGF21 plays a pivotal role in regulating neuronal oxidative stress and Ferroptosis. Aerobic exercise could increase the expression of FGF21, FGFR1, and PGC-1α, maintain the phosphorylation of AMPKα, and alleviate cardiac I/R-induced neuronal oxidative stress and Ferroptosis. These results confirm the protective effect of aerobic exercise against cardiac I/R-induced brain injury and provide an experimental basis for studying the relationship between exercise and the "heart-brain axis."

Aerobic exercise; Cardiac ischemia/reperfusion; FGF21; Ferroptosis; Oxidative stress; Paraventricular nucleus.